Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences and Pharmacy, St. Louis, MO, USA.
Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, MO, USA.
Sci Rep. 2024 Apr 10;14(1):8401. doi: 10.1038/s41598-024-58945-4.
REV-ERBα, a therapeutically promising nuclear hormone receptor, plays a crucial role in regulating various physiological processes such as the circadian clock, inflammation, and metabolism. However, the availability of chemical probes to investigate the pharmacology of this receptor is limited, with SR8278 being the only identified synthetic antagonist. Moreover, no X-ray crystal structures are currently available that demonstrate the binding of REV-ERBα to antagonist ligands. This lack of structural information impedes the development of targeted therapeutics. To address this issue, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the binding pathway of SR8278 to REV-ERBα. For comparison, we also used GaMD to observe the ligand binding process of STL1267, for which an X-ray structure is available. GaMD simulations successfully captured the binding of both ligands to the receptor's orthosteric site and predicted the ligand binding pathway and important amino acid residues involved in the antagonist SR8278 binding. This study highlights the effectiveness of GaMD in investigating protein-ligand interactions, particularly in the context of drug recognition for nuclear hormone receptors.
REV-ERBα 是一种有治疗前景的核激素受体，在调节昼夜节律、炎症和代谢等各种生理过程中发挥着关键作用。然而，用于研究该受体药理学的化学探针可用性有限，只有 SR8278 被鉴定为合成拮抗剂。此外，目前尚无 X 射线晶体结构显示 REV-ERBα 与拮抗剂配体的结合。这种缺乏结构信息的情况阻碍了靶向治疗药物的开发。为了解决这个问题，我们采用高斯加速分子动力学 (GaMD) 模拟来研究 SR8278 与 REV-ERBα 的结合途径。为了进行比较，我们还使用 GaMD 观察了具有 X 射线结构的 STL1267 的配体结合过程。GaMD 模拟成功捕获了两种配体与受体的正位点的结合，并预测了配体结合途径以及涉及拮抗剂 SR8278 结合的重要氨基酸残基。这项研究强调了 GaMD 在研究蛋白质-配体相互作用方面的有效性，特别是在核激素受体的药物识别方面。
